Sequence variants in SPAST, SPG3A and HSPD1 in hereditary spastic paraplegia

Svenstrup, Kirsten; Bross, Peter; Koefoed, Pernille; Hjermind, Lena E.; Eiberg, Hans; Born, Alfred Peter; Vissing, John; Gyllenborg, Jesper; Nørremølle, Anne; Hasholt, Lis; Nielsen, Jørgen E.

doi:10.1016/j.jns.2009.04.024

Cited by 16 publications

(11 citation statements)

References 34 publications

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“…Although several large cohorts of patients with mutant ATL1 gene were reported [17, 21, 27, 29, 32, 36, 45, 50, 54, 56], a genotype-phenotype correlation still remains unclear. Here, we reanalysed the observations on 142 families and confirmed three previously reported observations.…”

Section: Discussionmentioning

confidence: 99%

Clinical features and genotype-phenotype correlation analysis in patients with ATL1 mutations: A literature reanalysis

Zhao

Liu

2017

Transl Neurodegener

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BackgroundThe hereditary spastic paraplegias (HSPs) are a group of clinically and genetically heterogeneous disorders. Approximately 10% of the autosomal dominant (AD) HSPs (ADHSPs) have the spastic paraplegia 3A (SPG3A) genotype which is caused by ATL1 gene mutations. Currently there are more than 60 reported ATL1 gene mutations and the genotype-phenotype correlation remains unclear. The study aims to investigate the genotype-phenotype correlation in SPG3A patients.MethodsWe performed a reanalysis of the clinical features and genotype-phenotype correlations in 51 reported studies exhibiting an ATL1 gene mutation.ResultsMost HSPs-SPG3A patients exhibited an early age at onset (AAO) of <10 years old, and showed an autosomal dominant pure spastic paraplegia. We found that 14% of the HSPs-SPG3A patients presented complicated phenotypes, with distal atrophy being the most common complicated symptom. The AAO of each mutation group was not statistically significant (P > 0.05). The mutational spectrum associated with ATL1 gene mutation is wide, and most mutations are missense mutations, but do not involve the functional motif of ATL1 gene encoded atlastin-1 protein.ConclusionsOur findings indicate that there is no clear genotype-phenotype correlation in HSPs-SPG3A patients. We also find that exons 4, 7, 8 and 12 are mutation hotspots in ATL1 gene.Electronic supplementary materialThe online version of this article (doi:10.1186/s40035-017-0079-3) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Clinical features and genotype-phenotype correlation analysis in patients with ATL1 mutations: A literature reanalysis

Zhao

Liu

2017

Transl Neurodegener

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“…However, as the genetic complementation test showed a mild functional impairment (See Section Functional analysis in vivo ), this variation may be disease-associated with reduced penetrance. The most frequently observed amino acid variation in HSP60, HSP60-p.Gly563Ala, has been found in homozygous form in one sporadic Danish spastic paraplegia patient (Svenstrup et al, 2009). Frequency analysis of this polymorphisms in Danish controls showed an allele frequency of 1.3% and similar allele frequencies were observed in all ethnic groups in the ExAC database.…”

Section: Potential Disease-association Of Other Missense Variations Imentioning

confidence: 99%

Disease-Associated Mutations in the HSPD1 Gene Encoding the Large Subunit of the Mitochondrial HSP60/HSP10 Chaperonin Complex

Bross

Fernández‐Guerra

2016

Front. Mol. Biosci.

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Heat shock protein 60 (HSP60) forms together with heat shock protein 10 (HSP10) double-barrel chaperonin complexes that are essential for folding to the native state of proteins in the mitochondrial matrix space. Two extremely rare monogenic disorders have been described that are caused by missense mutations in the HSPD1 gene that encodes the HSP60 subunit of the HSP60/HSP10 chaperonin complex. Investigations of the molecular mechanisms underlying these disorders have revealed that different degrees of reduced HSP60 function produce distinct neurological phenotypes. While mutations with deleterious or strong dominant negative effects are not compatible with life, HSPD1 gene variations found in the human population impair HSP60 function and depending on the mechanism and degree of HSP60 dys- and mal-function cause different phenotypes. We here summarize the knowledge on the effects of disturbances of the function of the HSP60/HSP10 chaperonin complex by disease-associated mutations.

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“…More than 30 hereditary spastic paraplegia gene loci have been mapped, and specific mutations that result in disease have been identified in 17 different genes. Mutations in the HSPD1 gene are among the more rare causes of the disease (Svenstrup et al 2009). …”

Section: Introductionmentioning

confidence: 99%

Inactivation of the hereditary spastic paraplegia-associated Hspd1 gene encoding the Hsp60 chaperone results in early embryonic lethality in mice

Christensen

Nielsen

Hansen

et al. 2010

Cell Stress and Chaperones

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The mitochondrial Hsp60 chaperonin plays an important role in sustaining cellular viability. Its dysfunction is related to inherited forms of the human diseases spastic paraplegia and hypomyelinating leukodystrophy. However, it is unknown whether the requirement for Hsp60 is neuron specific or whether a complete loss of the protein will impair mammalian development and postnatal survival. In this study, we describe the generation and characterization of a mutant mouse line bearing an inactivating genetrap insertion in the Hspd1 gene encoding Hsp60. We found that heterozygous mice were born at the expected ratio compared to wild-type mice and displayed no obvious phenotype deficits. Using quantitative reverse transcription PCR, we found significantly decreased levels of the Hspd1 transcript in all of the tissues examined, demonstrating that the inactivation of the Hspd1 gene is efficient. By Western blot analysis, we found that the amount of Hsp60 protein, compared to either cytosolic tubulin or mitochondrial voltage-dependent anion-selective channel protein 1/porin, was decreased as well. The expression of the nearby Hspe1 gene, which encodes the Hsp10 co-chaperonin, was concomitantly down regulated in the liver, and the protein levels in all tissues except the brain were reduced. Homozygous Hspd1 mutant embryos, however, died shortly after implantation (day 6.5 to 7.5 of gestation, Theiler stages 9-10). Our results demonstrate that Hspd1 is an essential gene for early embryonic development in mice, while reducing the amount of Hsp60 by inactivation of one allele of the gene is compatible with survival to term as well as postnatal life.

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Sequence variants in SPAST, SPG3A and HSPD1 in hereditary spastic paraplegia

Cited by 16 publications

References 34 publications

Clinical features and genotype-phenotype correlation analysis in patients with ATL1 mutations: A literature reanalysis

Clinical features and genotype-phenotype correlation analysis in patients with ATL1 mutations: A literature reanalysis

Disease-Associated Mutations in the HSPD1 Gene Encoding the Large Subunit of the Mitochondrial HSP60/HSP10 Chaperonin Complex

Inactivation of the hereditary spastic paraplegia-associated Hspd1 gene encoding the Hsp60 chaperone results in early embryonic lethality in mice

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